Certain 6,7-dihydro-pyrido{8 1,2-d{9 {8 1,4,6{9 -benzodiazocines and 6 h-pyrido{8 1,2-c{9 {8 1,3,5{9 -benzoxadiazepines

ABSTRACT

EXHIBIT CENTRAL NERVOUS SYSTEM STIMULATING PROPERTIES AND ACT AS MUSCLE RELAXANTS.   Compounds of the formula

Emile [1 1 1111 3,856,8M Yale et el. Dec. 24, 1974 [54] CERTAIN3,565,914 2/1971 Yalc et al. 260/296 H 6,7-DllllYDRO-IPYRTDO[11,2-D]1,4,6]- lBIENZODlIAZOCINES AND 6 llll-PYIRIDO[ 1,2-C 1,3,5]-BENZOXADHAZEPINES Inventors: Harry Louis Yale, New Brunswick;

Ramesh B. Petigara, Somerset, both of N.J.

E. R. Squibb & Sons, llnc., Princeton, NJ.

Filed: Apr. 4, 1973 Appl. No.: 347,939

Assignee:

References Cited UNITED STATES PATENTS 3/1964 Yale et al. 260/296 HPrimary ExaminerAlan L. Rotman Attorney, Agent, or Firm L. S. Levinson[57] ABSTRACT Compounds of the formula exhibit central nervous systemstimulating properties and act as muscle relaxants.

2 Claims, N0 Drawings CERTAIN 6,7-lDllll-llYDRO-PYRIDO[1,2-D][1,4,6]-BIENZODIAZOCINES AND 6 ll-l-PYRllDOl 1,2-C][l,3,5]-BENZOXADIAZEFINESOBJECTS OF THE INVENTION object is to provide a method for thepreparation ofboth the intermediate and the final compounds of thepresent invention. Still another object is to provide a method for theadministration of the final compounds of the invention. A still furtherobject is to provide pharmaceutical compositions containing as activeingredients the final compounds of the present invention. These andother objects of the present invention will be apparent from thefollowing description.

SUMMARY OF THE INVENTION The compounds of the present invention have thefollowing formula wherein m may be 1 or 2 R may be hydrogen, halogen (F,Cl, Br, or 1), alkyl of from one to four carbons, alkoxy of from 1 to 4carbons, alkylmercapto of from one to four carbons, alkylsulfonylwherein the alkyl radical has from one to four carbons, phenyl,phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radicalmay have from one to four carbons, trifluoromethyl, monosubstitutedphenyl or mono-substituted phenyloxy wherein the substituent may behalogen F, Cl, Br or I), alkyl of from one to four carbons, alkoxy offrom one to four carbons or trifluoromethyl; provided that R occupiesthe position para to the carbon atom joined to oxygen when R isalkylsulfonyl, sulfamoyl, dialkylamidosulfonyl, phenyl, phenoxy,mono-substituted phenyl or mono-substituted phenoxy;

n may be 0 or 1;

and R" may be alkyl of from one to four carbons. or hydrogen andpharmaceutically acceptable acid-addition salts thereof.

The foregoing compounds possess central nervous system stimulatingproperties and act as muscle relaxants.

DETAILED DESCRIPTION The final compound I of the present invention maybe prepared by reacting a 2-aminopyridine 11 wherein R is as previouslydefined with an obromophenoxyalkylene halide Ill wherein R is aspreviously defined and X is chlorine or bromine. This reaction takesplace in any solvent or solvent mixture in which the reactants can bedissolved and which has a boiling point of at least about C. Typicalsolvents are aromatic hydrocarbons, ethers, aliphatic alcohols oraryl-substituted aliphatic alcohols. Toluene and xylene are examples ofsuitable aromatic hydrocarbons. Monomethyl ether of diethylene glycol,dimethyl ether of diethylene glycol (diglyme), monomethyl ether ofethylene glycol or dimethyl ether of ethylene glycol (glyme) areexamples of suitable ethers. n-Amyl alco hol is an example of a suitablealiphatic alcohol, while benzyl alcohol is an example of a suitablearylsubstituted aliphatic alcohol. Heating compounds [I and III in asolvent as described above, or a mixture thereof, at temperatures fromabout 100 to about 140C for a period of several hours, typically fromabout 3 to about 24 hours produces a p yridinium compound IV. Thelatteris converted to an imino compound V by treating with a watermiscible alcohol and an alkali metal alkoxide of up to 3 carbon atoms oran alkali metal carbonate. The reaction takes place at room temperatureover a period of from about 1 to about 4 hours. Compound V may beconverted to the final compound I by treating with a water misciblealcohol and an alkali metal alkoxide of up to three carbons in thepresence of copper at a temperature of from about 60 to about forseveral hours, typically from about 2 to about 4 hours. Alternatively,1V may be converted directly to I by heating at a temperature of fromabout 60 to about 120C for several hours, typically from about 1 toabout 4 hours in the presence of potassium carbonate and copper in asolvent such as dimethylformamide, dimethylacetamide, dichlorobenzene,trichlorobenzene, or diethylbenzene. Alternatively, however, 1V may beconverted directly to l by heating at a temperature of from about 60 toabout 120C for several hours, typically from about 1 to about 4 hours inthe presence of an alkali metal hydroxide, alkali metal carbonate,tris-alkali metal phosphate, alkali metal metaborate or alkali metaltetra-borate in a solvent comprising a mixture of water and a water IIIThe intermediates of formula lll wherein n is may be prepared byrefluxing about equimolar amounts of a l,l-dibromoalkane or al-bromo-l-chloralkane of one to four carbons Vl with a saturatedsolution of Na S0,, for a period of from about 40 to about 120 hours.The resulting l-bromoalkane-l-sodium sulfonate Vll is then reacted byheating with about equimolar amounts of an o-bromophenol Vlll in thepresence of aqueous alkali to yield a sodiumo-bromophenoxyalkylenesulfonate lX. Treatment of the latter with PCl orPBr 5 at ambient temperature yields the corresponding 0-bromophenoxy-alkyl chloride or bromide X. The foregoing reactionsequence is illustrated by the following equations IX X Theintermediates of formula lll wherein n is 1 may be prepared by reactinga l-bromo-Z-chloroalkane of formula Xl with about equimolar amounts of acompound of formula Vlll in the presence of aqueous alkali.Alternatively, a compound of formula XII may be prepared by reacting ano-bromophenoxyalkanol Xlll with PCI or PBr The foregoing reactionsequence is illustrated by the following equations XIII Compounds offormula Vlll wherein R is fluorine, CF or alkylthio wherein the alkylradical is from one to four carbons may be prepared by brominating afluorophenol, a trifluoromethylphenol or an alkylthiophenol in thepresence of Fe catalyst at from about 30 to about 40C. From about 1 partby weight of iron to about 10 parts by weight of the substituted phenolare generally used. A halogenated solvent, e.g., chloroform or carbontetrachloride, may be used in those cases where the substituted phenolis a solid at reaction temperatures. The foregoing reaction sequence isillustrated by the following equations HO- HO- Fe catalyst Compounds offormula VIII wherein R in the position para to the hydroxyl group isalkylsulfone, sulfamyl or dialkylsulfamyl may be prepared by thefollowing sequence of reactions The chlorine atom in the compound offormula XIV, XV or XVI is replaced by a hydroxyl group by following theprocedure of Pettit et al., J. Chem. Soc., 3852, 1954. Treatment oftheresulting hydroxy derivative according to the procedure of Yale et al.,J. Med. Chem., 13, 713, 1970, converts the nitro group to an aminogroup. Subjecting the resulting amino derivative to the Sandmeyerreaction serves to replace the amino group by a hydroxyl group to givethe compound Br R wherein R is sulfamoyl, alkylsulfonyl ordialkylamidosulfonyl wherein the alkyl groups have from one to fourcarbon atoms.

Compounds of formula Vlll wherein R is phenyl or phenoxy are prepared bybromination of a hydroxybiphenyl or of a hydroxydiphenyl ether accordingto the procedure of Bradsher et al., J. Org. Chem, 22, 500 (1957) andJanssen et al., J. Org. Chem, 20, 1326-9 (1955). The foregoing reactionsequence is illustrated by the following equations Br: Br

Compounds of formula Vlll wherein R is halophenyl, alkylphenyl,alkoxyphenyl, or trifluoromethylphenyl may be prepared by reacting an R-substituted aniline with phenol according to the procedure of Hirsch,Ber. 23, 3710 (1890). Bromination of the resulting p-(substitutedphenyl)Phenol by the pro cedure of Bradsher et al., supra, gives theo-bromo-p- (substituted phenyl)phenol. The foregoing reaction sequenceis illustrated by the following equations:

1) HONO O NH2 2 OH R Br I{'=hlalogen. 3) Br: lkoxy or CF; X/

Compounds of formula VIII wherein R is halophenoxy, alkylphenoxy, ortrifluoromethylphenoxy may be prepared by the methods of OrganicSyntheses Coll. Vol. III, p. 566 and Coll. Vol. II, p. 455; followed bythe methods of Janssen et al. and Bradsher et al., supra. The reactionsequence is as follows:

Compounds of formula Vlll wherein R is alkoxysubstituted phenyl may beprepared by reacting pchloronitrobenzene with an alkoxy-substitutedphenol in the presence of KOH, reducing the resulting p-(alkoxyphenoxy)-nitrobenzene to the corresponding amine and treating thelatter with nitrous acid and water to convert the amino group to thehydroxyl group, and brominating the resulting p-(alkoxyphenoxy)phenol.The reaction sequence is as follows:

oiN Ko 11 Starting materials of formula 11 wherein R is phenyl,halo-substituted phenyl, alkyl-substituted phenyl, alkoxy-substitutedphenyl or trifluoromethyl-substituted phenyl may be prepared by heating3-(N-acetamido-N- nitroso)pyridine XXIV with benzene, halo-substitutedbenzene, alkyl-substituted benzene, alkoxy-substituted benzene ortrifluoromethyl-substituted benzene according to the procedure ofHaworth et al., J. Chem. Soc., 1940, 372, and J. Chem. Soc., 1954,4516.The product XXV is a 3-substituted pyridine wherein theN-aeetamido-N-nitroso radical is replaced by a phenyl or substitutedphenyl radical derived from the compound with which the3-(N-acetamido-N- nitroso)pyridine is heated. The product of formula XXVis treated with sodamide according to the procedure of Chichibabin etal., J. Russ, Phys. Chem. Soc. 46, I216 (1914),Chem. Zentr. II, 1064(l9l5),t0 give the aminopyridines XXXll and XXXllI.

lilo... 4 B e e a R=lmlo,n,lkyl, alkoxst i. CF] or 1y rogon N ENII:

XXXIII XXXH X=llalogen z -1" llzN- 0 Compounds of formula [I wherein Ris halophenyl may be prepared by reacting a halo-substituted N-nitrosoacetanilide with pyridine according to the procedure of Bachmannet al., Organic Reactions, Vol. 11, pp. 224-261. The resultinghalo-substituted phenylpyridine is treated with sodamide according tothe procedure of Chichibabin et al., supra. to give the desiredhalophenylsubstituted 2-aminopyridine. The reaction sequence is asfollows:

XXVI XXVIl' 2:11, or alkoxy Compounds of formula 11 wherein R isphenylmercapto, alkylmercapto, benzyl, phenethyl or phenoxy may beprepared by treating a substituted pyridine of the formula Didi N 9wherein R is a phenylmercapto, alkylmercapto, benzyl, phenethyl orphenoxy substituent occupying the 3-, 4-, 5- or 6-position, withsodamide according to the procedure of Chichibabin et al., supra.

The compounds of the present invention may be administered to mammalianspecies as central nervous system stimulants and as muscle relaxants. Inthe rat, responses to the stimulant activity of the compounds of thepresent invention include increased .activity and body tremors. Themuscle relaxant properties manifest themselves by responses that includedecreased limb tone, decreased grip strength, and limb paralysis. Inboth the stimulant and muscle relaxant activities, the onset of activityis rapid, i.e., within about minutes; the activity persists for about 2hours or longer. In the rat the dosage range varies from about 6.25 toabout 50 mg/kg for both activities, while in humans the dosage rangevaries from about 40 to about 2,000 mg. daily in about four divideddoses for both activities.

In addition to serving as intermediatesfor the preparation of compoundsof formula I, the pyridinium compounds of formula IV are themselveseffective bactericides.

Microbial bioassays, as described in The Microbial World, by R. Y.Stanier, M. Doudoroff and E. A. Adelberg, Prentice-Hall, Inc., EmglewoodCliffs, N. J., 3rd Ed., p. 858, are employed to determine thebactericidal properties of the pyridinium compounds IV of thisinvention. The bacteria employed include Staphyloc0ccus aureus, 1,Streptococcus pyogenes, 2, Salmonella schottmuelleri, 3, Salmonellagallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6,Escherichia coli,

of active compound in such therapeutically useful com- 7, Pasturellamultocida, 8, and Mycobacterium tuberculosis, 9.

In the procedure, a sterile agar plate is seeded with the test organism,and then a number of glass cylinders are placed on its surface, forminga series of little cups. A known dilution of the compounds of thisinvention is added to each cup and the entire plate is then incubateduntil significant bacterial growth has occurred. The compounds of thisinvention diffuse out of the cup into the surrounding agar and produce azone of inhibition. In this fashion it is possible to' find the minimuminhibiting concentration (mic), of the compound that produces arecognizable zone of inhibition. The following summarizes the data.

The compounds of the present invention in the described dosages may beadministered orally; however, other routes such as intraperitoneally,subcutaneously, intramuscularly or intravenously may be employed.

The active compounds of the present invention are orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or they may be enpositions or preparations is such that asuitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of Wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmaybe present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills or capsules may be coatedwith shellac, sugar, or both. A syrup or elixir may contain the activecompounds, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit'form should bepharmaceutically pure and substantially non-toxic in the amountsemployed.

As to the pharmaceutically acceptable salts, those coming within thepurview of this invention include the pharmaceutically acceptableacid-addition salts. Acids useful for preparing these acid-additionsalts include, inter alia, inorganic acids, such as the hydrohalic acids(e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid,and phosphoric acid, and organic acids such as maleic, fumaric,tartaric, citric, acetic, benzoic, Z-acetoxybenzoic, salicylic, succinicacid, theophylline, 8-chlorotheophylline, p-aminobenzoic,pacetamidobenzoic, or methanesulfonic.

The following examples illustrate the present invention without,however, limiting the same thereto. All temperatures in the followingexamples as well as the preceding description are expressed indegreesCentigrade.

EXAMPLE I 6H-Pyrido[1,2-c][1,3,5]benzoxadiazepine, hydrochloride A.Sodium bromomethane sulfonate B. (o-Bromophenoxy)methane sulfonic acid,sodium salt To a solution of 61.3 g of o-bromophenol in aqueous NaOHsolution [15.5 g of sodium hydroxide in 61 m1 of water], is added 68.0 gof sodium bromomethanesul fonate. While stirring, the reaction mixtureis slowly heated to 150, in an oil bath, with simultaneous removal ofwater. In about 3 hours of heating, 61 ml of water is distilled, and theresidue solidifies; this is further heated at 200 for about 2.5 hours.The solid is dissolved in 800 ml of warm water, the solution filteredand the filtrate adjusted to pH 5 and washed with 2 X 200 ml of ether.The aqueous phase is concentrated to 600 ml and cooled. The crystallinesolid is filtered and dried in vacuo to give 63.3 g of the product,which is recrystallized from 600 ml of 90% aqueous ethanol to furnishabout 57.5 g of the title product, mp about 282284.

C. o-Bromo-a-chloroanisole A mixture of 29.0 g ofo-bromo-a-chloroanisole and 50.0 g of PCl are thoroughly blended in amortar. After about minutes of continuous mixing, the mixture partlymelts, a vigorous reaction occurs, and the whole turns to a liquid. Themixture is kept minutes with occasional stirring, 700 ml of ether isadded (a white solid separates) and the mixture is poured into 750 g ofcrushed ice. The ether solution is separated, washed, dried, andconcentrated in vacuo to give about 21.0 g of a liquid residue. Thisdistilled under reduced pressure to give about 19.5 g of the colorlessliquid product, b 7475, n 1.5799.

D. 2-Amino-l-[(o-bromophenoxy)methyl]pyridinium chloride To a solutionof 7.1 g of 2-aminopyridine in 35 ml of xylene is added, dropwise, asolution of 11.1 g of obromo-achloroanisole in 45 ml of xylene. Themixture is warmed at 50 for 5 minutes and allowed to stir for 40 hoursat room temperature. The solid is filtered and dried to give about 16.0g of the product. This is recrystallized from 2-propanol to give about14.0 g ofthe title product, mp 17l173.

E. 6H-Pyrido[1,2-c][1,3,5]benzoxadiazepine A mixture of 9.5 g of2-amino-1-[(o-bromophenoxy)-methyl]pyridinium chloride, 8.3 g ofpotassium carbonate, 0.4 g of copper-bronze in 150 ml of n-propanol and25 ml of water under N is heated under reflux for 12 hours whilestirring. The mixture is filtered hot and the deep yellow filtrate isconcentrated to dryness. The residue is dissolved in 400 ml of ether,the ether solution is washed, dried and the solvent removed to giveabout 6.4 g of the crude yellow product. This is recrystallized fromcyclohexane to give about 3.6 g of the title product, mp about 125-127.

F. 6H-Pyrido[1,2-c][1,3,51benzoxadiazepine, hydrochloride To a solutionof 1.0 g of 6H-pyrido[l,2-c][1,3,5]- benzoxadiazepine in 20 ml of2-propanol is added 5.0 ml of 4.2N 2-propanolic hydrogen chloride. Tothe clear solution is added anhydrous ether until a turbidity forms. Thepale yellow crystalline solid is filtered and recrystallized fromacetonitrile to give about 1.0 g of the title compound, mp about 232234.

EXAMPLE 2 6H-Pyridol l ,2,-c][ 1,3,5 l-benzoxadiazcpine A B.6H-Pyrido[1,2-c][1,3,5]-benzoxadiazepine To a solution of 4.65 g of theproduct from A in ml of n-propanol is added 0.20 g of copper bronze and5.6 g of micronized, anhydrous, potassium carbonate, and the stirredsuspension is heated under reflux for about ten hours. Workup as inExample 1E gives about 2.78 g of the title compound, m.p. about l25-l27.

EXAMPLES 31 3 Following the procedure of example 1 but substituting forZ-aminopyridine in part D the substituted pyridine listed below, thereis obtained the correspondingly substituted compound of formula [Vwherein R and R" are hydrogen and n=O which compound is then convertedto the correspondingly substituted compound of formula 1:

CIIKCIIg-I C H1) 3 C Hz EXAMPLES 14-23 N o113 oim.. l-rvu- 1 20. (Born 11i... z 22. S D\N NHz 23. |C(CH3)3 EXAMPLE 24 2-Chloro-6 -H-pyrido[l,2-c][1,3,5]benzoxadiazepine hydrochloride A.2-Bromo-4-chlorophenoxymethanesulfonic acid, sodium salt To a solutionof 75.0 g of 2-bromo-4-chlorophenol in 65 ml of water is added 16.0 g ofsodium hydroxide and 100 g of bromomethanesulfonic acid, sodium salt.The procedure of Example 1, part B, is followed to give about 74.5 g of2-bromo-4-chlorophenoxymethanesulfonic acid, sodium salt, m.p. above315.

B. 2-Bromo-4-chlorophenyl chloromethyl ether A mixture of 71.0 g of theproduct from A and 1 10.0 g of phosphorus pentachloride is reacted as inExample 1, part C, to give about 55.7 g of 2-bromo-4- chlorophenylchloromethyl ether, m.p. about 56.057.5.

C. 2-Amino-1-[2-bromo-4-chlorophenoxy)methyl]- pyridinium chloride To asolution of 14.1 g of 2-aminopyridine in 180 ml of warm, anhydrousxylene is added 25.6 g of the product from B in ml of anhydrous xyleneand the mixture is stirred for about 4 hours at room temperature andthen at for about 2 hours to give about 33.0 g of2-amino-1-[(2-bromo-4-chlorophenoxy)methyl]- pyridinium chloride, m.p.about 237-239.

D. 2-Chloro-6H-pyrido[1,2-c][1,3,5]benzoxadiazepine hydrochloride Amixture of 14.0 g of 2-amino-l-[(2-bromo-4-chlorophenoxy)methyl]pyridinium chloride, 11.1 g of micronized,anhydrous potassium carbonate, 0.4 g of copper bronze, and 350 ml ofanhydrous n-propanol is EXAMLPES 2564 Following the procedure of example24 but substituting for 2-bromo-4-chlorophenol the substituted 2-bromophenol listed in column I, there is obtained the correspondinglysubstituted compound from parts B and C, and finally the compound of thefollowing formula wherein R and the position it occupies are indicatedin column ll.

It H

wherein R is as indicated in column ll.

Example I II (11") 65 1,1-dibromoethanc CI I;

66 1,l-dibromoisohutmte-... OH;

EXAMPLES 71-97 Following the procedure of example 1 but substituting for2-aminopyrid ine in part D an equivalent amount 25 of the substitutedpyridine listed in column I, there is obtained the correspondinglysubstituted pyridinium Example I ll 25. 2.4-dibromophenol 2-bromo 26.2,6-dibromophenol 4-bromo 27. 2-bromo-4-iodophenol 2-iodo 28.2-bromo-4-methylphenol Z-methyl 29. 2-bromo-6methylphenol 4-methyl 30.2-bromo-3-chlorophenol l-chloro 3 l. Z-bromo-S-chlorophenol 3-chloro 32.2-bromo-4-n-butylphenol Z-n-butyl 33. 2-bromo-4-i-butylphenol Z-i-butyl34. 2-bromo4-n-butoxyphenol 2-n-butoxy 35. 2-bromo-6-fluorophenol4-fluoro 36. 2-bromo-5-fluorophenol 3-fluoro 37. 2-bro'mo-4-fluorophenolZ-fluoro 38. 2-bromo-4-(methylmercapto)phenol Z-(methylmereapto) 39.6-bromo-a,a,a-trifluoro-m-cresol 3-trifluoromethyl 42.2-bromo-3-(ethylmercapto)phenol l-(ethylmercaplo) 43.2-bromo-4-phenylphenol Z-phenyl 44. Z-bromo-3-trifluoromethylphenoll-trifluoromethyl 46. 2-hromo-4-phenoxyphenol 2-phenoxy 48. 2-bromo-4-(ochlorophenyl)phenol Z-(o-chlorophenyl) 49.2-bromo-4-(m-bromophcnyUphenol Z-(m-bromophenyl) 50.2-bromo-4-(p-iodophenyl)phenol 2-(p-iodophcnyl) 5l.2-bromo-4-(m-fluorophenyloxylphenoI 2-(m-fluorophenyloxy) S2.2-bromo-4-(p-chlorophenyloxy)phenol 2-(p'chlorophenyloxy) 53.2-bromo-4-(m-iodiphenyloxy)phenol 2-(m-iodophenyloxy) 54.2-bromo-4-(o-bromophenyloxy)phenol 2-(o-bromophenyloxy) 55.2-bromo-4-(o-methylphenyl)phenol Z-(o-methylphenyl) 56.2-bromo-4-(m-ethylphenyl)phenol 2 (m ethylphenyl) 57.2-bromo-4-(p-methoxyphenyl)phenol Z-(p-methoxyphenyl) 58.2-hromo-4-(o-propoxyphenyl)phenol 2-(o-propoxyphenyl) 59.2-hromo-4-(p-trifluoromethylphenyU- Z-(ntrifluoromethylphenol phenyl 60.2-hromo-4-sulfumoylpheno] Z-sulfamoyl 6|.2-hromo-4dimelhylamidosulfonyl- Z-dimethylamidophenol sulfonyl 62.2gbronlio-4-dihutylamidosulfonyl 2-dibutylamidosu|fonyl p eno 63.2-bromo-4-ethylsulfonylphenol 2-cthylsulfonyl 64.2-bromo-4-propylsulfonyIphenol Z-propylsulfonyl EXAMPLES 65-68 Followingthe procedure of example l but substitutchloride (from part D), thecorrespondingly substituted base (from part E), and the correspondinglysubstiing for dibromomethane the compound listed in col- 65 tutedhydrochloride salt (from part F). The substituent umn I, there isobtained the compound of the following formula and the position itoccupies in the final product of the formula KAI ll? U lll U W and 50.0g of o-bromophenyl 2-chloropropyl ether and 200 ml of anhydrous tolueneis heated under reflux for about 6 hours, cooled, and the crystallineproduct filtered to give about 73.2 g of 2-amino-1-[2-(obromophenoxy-l-methylethyl)]-5- phenethylpyridmium chloride as a colorless,crystalline are indicated in column ll. solid.

I ll

71. 2-amino-3-phenylpyridine ll-phenyl 72.2-amino-3-(o-chlorophenyl)pyridine l l-(o-chlorophenyl) 73.2-amino4-(m-brornophenyl)pyridine lO-(m-bromophenyl) 74.2-amino-5-(p-fluorophenyl)pyridine 9-(p-fluorophenyl) 75.2-amino-6-(m-iodophenyl)pyridine 8-(m'iodophenyl) 76.2-amino-3-(o-tolyl)pyridine ll-(o-tolyl) 77.2'amino-5-(p'ethylphenyUpyridine 9-(p-ethylphenyl) 78.2-amino-3-lm-propoxyphenyl)pyridine l l-(m-propoxyphenyl) 79.2amino-5-(p-butoxyphenyl)pyridine 9-(p-butoxyphenyl) 80.2-amino-3-(p-trifluoromethy l l-(p-trifluorophenyl)pyridinemethylphenyl) 81. 2-amino-3-(methylmercapto)pyridine ll-(methylmercapto)82. 2-amino-6-(phenylmercapto)pyridine 8-(phenylmercapto) 83.-Z-amino-S-(phenylmercapl )Py idine 9-(phenylmercapto) 84.2-amino-4-(phenylmercapto pyridine IO-(phenylmercapto) 85.2-amino-3-(phenylmercapto)pyridine l l-(phenylmercapto) 86.2-amino-6-(methylmercapto)pyridine B-(methylmercapto) 87.2-amino-5-(butylmercapto)pyridine 9-(butylmercapto) 88.2-amino-5-(propylmercapto)pyridine 9-(propylmercapto) 89.2-amino-4-(methylmercapto)pyridine IO-(methylmercapto) 90,2-amino-4-(ethylmercapto)pyridine lO-(ethylmercapto) 9 l.2-amino-4-(ethylmercapto )6- lO-(ethylmercaptomethylpyrldine S-methyl92. 2-amino-3-(phenethyl)pyridine l l-(phenethyl) 93.2-amino-4-benzylpyridine IO-benzyl 94. 2-amino-5 (phenethyl)pyridine9-(phcnethyl) 95. Z-amino--benzylpyridine 8-benzyl 96.2-amino-6-phenoxypyridine 8phenoxy 97. 2-amino-4-phenoxypyridinel0phenoxy EXAMPLE 98 6,7-Dihydro-7-methyl-10-phenethylpyrido[1,2- d l,4,6]benzox adiazocine A. o-Bromophenyl 2-chloropropyl ether To asolution of 23.0 g of sodium metal in 500 ml of absolute ethanol isadded in about 0.5 hour a solution of 173.0 g of o-bromophenol in 250 mlof absolute ethanol. The mixture is stirred and heated under reflux forabout 0.5 hour, cooled to 0, and treated, dropwise, with 157.5 g ofl-br0mo-2-chloropropane. Thelast addition requires about 1 hour. Themixture is stirred at 0 for about 2 hours and slowly warmed to refluxduring about 2 hours, heated under reflux for about 2' hours, filteredfrom the precipitated sodium bromide, and the filtrate is connected invacuo at to give about 240.2'

g of o-bromophenyl 2-chloropropyl ether as a mobile, colorless liquid.

B. Z-Aminol -[2'-(o-bromophenoxy-l -methylethyl)]-5- phenethylpyridiniumchloride A solution of 40.1 g of 2-amino-5-phenethylpyridine C.l-[2'-(o-Bromophenoxy-l -methylethyl)]-l ,2-dihydro-2-imino-5-phenethylpyridine D.6,7-Dihydro-7-methyl-lO-phenethylpyridol1,2- d H l ,4,6lbenzoxadiazocine The product from C, 3.69 g, 50 ml of anhydrousnpropanol, 2.8 g of anhydrous, micronized potassium carbonate, and 0.25g of copper bronze are stirred and heated under reflux for about 6hours, filtered hot, and the deep, yellow colored filtrate isconcentrated to dryness in vacuo at 40. The deep yellow-colored solid isrecrystallized from ligroin to give about 2.42 g of'6,7-dihydro-7-methyl-l0-phenethylpyrido[ l,2-d][ 1,4,6]- benzoxadiazocine.

Example 99 Preparation of capsule formulation Magnesium stearate 5Example 160 and other flavors and dyes may be used in place of thoselisted above.

What is claimed is: 1. A compound of the formula Preparation of tabletformulation lngredient Milligrams per Tablet 2-Chloro-6H-pyrido l,2-c Il,3,5 1 benzoxadiazepine hydrochloride Lactose Corn starch (for mix)Corn starch (for paste) Magnesium stearate The active ingredient,lactose and corn starch (for mix) are blended together. The corn starch(for paste) is suspended in water at a ratio of grams of corn starch per80 milliliters of water and heated with stirring to form a paste. Thispaste is then used to granulate the mixed powders. The wet granules arepassed through a No. 8 screen and dried at 120F. The dry granules arepassed through a No. 16 screen. The mixture is lubri-. cated withmagnesiumstearate and compressed into tablets in a suitable tabletingmachine. Each tablet contains 300 milligrams of active ingredient.

The sorbitol solution is added to 40 milliliters of distilled water andthe active ingredient is suspended therein. The sucaryl, saccharin,sodium benzoate, flavor and dye are added and dissolved in the abovesolution. The volume is adjusted to 100 milliliters with distilledwater.

Other ingredients may replace those listed in the above formulation. Forexample, a suspending agent S such as bentomte magma, tragacanth,carboxymethylcellulose, or methylcellulose'may be used. Phosphates,eitrates or tartrates may be added as buffers. Preservatlves may includethe parabens, sorbic acid and the like V H 1|! 7 0 20 lI(CII:)nO

N (lo-"w @R/ wherein m is 1 or 2 R is the same or different and ishydrogen, halogen (F, Cl, or Br), alkyl of from one to four carbons,alkoxy of from I to 4 carbons, alkylthio of from one to four carbons,benzyl, phenethyl, phenyl, phenoxy, phenylmercapto or mono-substitutedphenyl wherein the substituent may be halogen (F, Cl, Br or I), alkyl offrom one to four carbons, alkoxy of from 1 to four carbons, ortrifluoromethyl; provided that when R is halogen, R occupies only the 3-or S-position in the original 2-aminopyridine; R is hydrogen, halogen(F, Cl, Br or I), alkyl of from one to four carbons, alkoxy of from oneto four carbons, alkylmercapto of from one to four carbons,alkylsulfonyl wherein the alkyl radical has from one to four carbons,phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkylradical may have fromone to four carbons, trifluoromethyl,mono-substituted phenyl or monosubstituted phenyloxy wherein thesubstituent may be halogen (F, Cl, Br or I), alkyl of from one to fourcarbons, alkoxy of from one to four carbons of trifluoromethyl; providedthat R occupies the position para to the carbon atom joined to oxygenwhen R is alkylsulfonyl sulfamoyl, dialkylamidosulfonyl, phenyl,phenoxy, monosubstituted phenyl or mono'substituted phenoxy; n isOor l;

and R" is hydrogen or alkyl of from one to four car- 4 5 bons, andpharmaceutically acceptable acidaddition salts thereof. 2. A compoundaccording to claim 1 having the name 6l-l-pyrido[l,2-c][1,3,S1benzoxadiazepine.

Page 1 of 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENTNO. 3,856,801

DATED December 24, 1974 INVENTOR(S) Harry Louis Yale and Ramesh B.Petigara Column 2, line 1, after "halogen" insert Column 3, line 23 "Xshould read -.X Column 4, line 66, "S=alkyl" should read -Salkyl. Column7, formula XXV should read Column 9, line 26, "Emglewood" should readEnglewood. Column 11, line 27, after "This" insert is. Column 13 example14 should read NH Br 2 Column 14, line 32, "6-H" should read -6H-.Column 14, line 52, before "2-bromo" insert Column 15, example 53,"iodiphenyloxy" should read iodophenyloxy-. Column 16, example 68, "(CHCH should read (CH CH Column 17, the formula should read CH O 9 2 \N Itis certified that error appears in the ab0ve-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Page 2 of 2' UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 1 3 85 01 DATED December 24, 1974 vE 0 (5) 1 Harry Louis Yaleand Ramesh B. Petigara It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 17, line 53, "connected" should read concentrated--. Column 20,line 48, "of" should read -or-. Column 20, line 50, after"alkylsulfonyl" insert a Signed and ,Zrcalcd this seventh Day of0ct0'ber1975 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN' Arresting Officer Commissioner ofParenrsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 having the name 6H-pyrido(1, 2-c)(1,3,5)benzoxadiazepine. 